Tumor angiogenesis plays a critical role in the malignant tumor growth and metastasis. When tumors grow beyond 1 mm3, angiogenesis or generation of vascular arborizations by budding from existing vessels is necessary to provide enough blood for the survival of tumor cells. The growth speed and tendency of metastasis of tumors are associated with the level of neovascularization factors and the quantity of nascent microvessels. Since the hypothesis “anti-angiogenesis therapy” was put forward by Folkman in early 1970s, people have made considerable progress in this field, and inhibiting angiogenesis of tumors has been universally accepted as a new anticancer strategy.
Tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play significantly important roles in angiogenesis of tumors, and they are both important targets in blocking angiogenesis of tumors. Vascular endothelial growth factor (VEGF) is the foremost factor in vivo promoting the angiogenesis. The binding of VEGF with vascular endothelial growth factor receptor (VEGFR) in endothelial cells leads to various reactions of angiogenesis, such as cells proliferation, cells metastasis, the increase of vascular permeability, and the move of endothelial cells precursors out of marrow. VEGFR family comprises VEGFR1 (Flt-1), VEGFR2 (KDR/Flk-1) and VEGFR3 (Flt-4). Promotion of the angiogenesis is mainly mediated by the bonded VEGF and VEGFR2 (KDR/Flk-1). Numerous human tumors exhibit high VEGFR levels. Currently, more than 40 medicaments capable of inhibiting angiogenesis are in the clinical trial, such as monoclonal antibodies of VEGF and its receptor (VEGFR), and small molecular inhibitors of VEGFR tyrosine kinase. VEGF monoclonal antibody Avastin, which had been developing by Genetech for more than ten years, was approved for marketing in 2004. The efficacy of Avastin in combination with other medicaments on colon cancer, lung cancer and breast cancer has proved that the mechanism of Avastin as an anti-VEGF drug is feasible. Avastin also made outstanding contributions to the mechanism of anti-angiogenesis as an anti-cancer target.
The most remarkable drugs of small molecular VEGFR inhibitors in recent years include VEGFR inhibitor Vatalanib (PTK787) for the treatment of colon cancer developed by Novartis/Schering, and VEGFR and epidermal growth factor receptor (EGFR) double-target inhibitor Zactima (ZD-6474) for the treatment of relapsed/refractory non-small cell lung cancer developed by Astrazeneca. VEGF inhibitors gradually become new non-cytotoxic anticancer drugs with good application prospects. Compared with traditional cytotoxic drugs which inhibit the growth of tumors, angiogenesis targeting drugs are more specific and less toxic as well as helpful to overcome the drug resistance of tumors and can be used for the treatment of various tumors.
N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide (hereinafter referred to as “compound A”) is a new generation of tyrosine kinase inhibitor, the compound has the formula (I):

The above-mentioned compound is recorded in Chinese patent application No. 02138671.4, the content of which is herein incorporated by reference in its entirety. It has been found that compound A has very strong selective inhibition on VEGFR-2 in the enzyme level tests of tyrosine kinase receptors in different laboratories, IC50 of which was about 1 nM. In addition, it has certain selective inhibition activity on kinases Ret, VEGFR-1, PDGFR-β, c-kit, cSRC and so on. Pharmacodynamics research of human tumor transplanted in nude mice has found that the efficacy of compound A on colon cancer Ls174t transplanted in nude mice was distinctly better than PTK787; and the efficacy of compound A was improved when it was used in combination with oxaliplatin while the toxicity of which was not increased. Whether used alone or in combination, the efficacy of compound A was better than PTK787. It has also been found that the efficacy of compound A on non-small cell lung cancer A549 transplanted in nude mice was distinctly better than PTK787, the maximum efficacy of which was equivalent to ZD6474 at a customary dose. In the aspect of toxicity, compound A was well tolerated at the maximum dose of 400 mg/kg by nude mice.
However, during the research of the drug, it was found that N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide was not satisfying in some aspects, e.g. stability and bioavailability.